Dual membrane receptor degradation via folate receptor targeting chimera

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Cancer drug resistance is a major clinical challenge, often driven by complex signaling pathways involving membrane-bound receptors.
• Current mono-targeted therapies are frequently compromised by receptor cross-talk, leading to treatment failure.

Purpose of the Study:

• To develop a novel dual membrane receptor degradation strategy to overcome cancer drug resistance.
• To engineer Folate Receptor α Targeting Chimeras-dual (FolTAC-dual) for simultaneous degradation of specific receptor pairs.

Main Methods:

• Designed and optimized FolTAC-dual constructs, identifying a "string" format as most effective.
• Investigated binding affinity and degradation efficiency using mechanistic studies.
• Evaluated efficacy in preclinical models of HER2-positive breast cancer and immune checkpoint blockade resistance.

Main Results:

• FolTAC-dual demonstrated enhanced EGFR-binding affinity compared to conventional designs.
• EGFR/HER2 FolTAC-dual effectively counteracted resistance in HER2-positive breast cancer models.
• PD-L1/VISTA FolTAC-dual restored immune responses in resistant models.

Conclusions:

• FolTAC-dual represents a promising platform for dual-target degradation to combat cancer drug resistance.
• This strategy holds potential for clinical translation in various oncology settings.